Central Memory T Cells That Express High Level Of CD44 Mediate Strong Anti-Tumor Response Without Gvhd

Abstract

Several groups have demonstrated directly and indirectly that central memory T cells (TCM) have decreased ability to induce graft-versus-host disease (GVHD) compared with naïve T cells (TN). We have previously demonstrated that TCM expressing high level of CD44 (CD44high TCM) do not cause GVHD. In this study, we further defined the role of CD4+ and CD8+ subsets of this population in GVHD using the same GVHD model as we used previously (C57BL/6→BALB/c). While all CD4+ TN recipients developed lethal GVHD and died within 28 days after transplantation, none of the recipients of CD4+CD44high TCM developed GVHD and all survived more than 100 days after transplantation (P<0.01). Similarly, 36% of CD8+ TN recipients developed lethal GVHD but none of CD8+CD44high TCM recipients developed GVHD (P<0.05). One of the unique features of effector memory T cells (TEM) is that these cells are able to facilitate stem cell engraftment and mediate some degree of anti-tumor response without causing GVHD. To test the ability of TCM to deplete host radioresistant T cells, BALB/c recipients were lethally irradiated (8.5 Gy) and transplanted with 1x107 T-cell-depleted (TCD) bone marrow cells together with graded numbers of T cell subsets from C57BL/6. Host T cells persist in all mice receiving only TCD bone marrow cells. Addition of 1x105 of either TN or CD44high TCM to the graft led to 100% depletion of all host radioresistant T cells. In contrast, none of 1x105 TEM recipients and only 50% of 5x105 TEM recipients depleted all host radioresistant T cells. These data indicate that TN and CD44high TCM have equivalent abilities to deplete host radioresistant T cells and both of them are at least 5 times more potent than TEM. To test the ability of CD44high TCM to mediate anti-tumor effects, host-type leukemia/lymphoma cells (BCL1) cells were added to the stem cell graft. All recipients transplanted with TCD bone marrow together with BCL1 cells developed tumor and died within 28 days after transplantation. Addition of 1x104 TN and CD44high TCM protected 42% and 36% of the recipients from developing tumor respectively. In contrast, only 7% of TEM recipients were protected (P<0.05) at the same dose level. Similarly, addition of 1x105 TN and CD44high TCM protected 79% and 80% of the recipients from developing tumor respectively. However, only 25% of 1x105 TEM recipients were protected (P<0.01). These data indicate that TN and CD44high TCM have equal anti-tumor activity and both of them are at least 10 times more potent than TEM. Similar results were obtained in CD8 subset of CD44high TCM. A critical question is why CD44high TCM are able to kill host radioresistant T cells and tumor cells so efficiently without inducing GVHD. Even though CD44high TCM were able to respond to alloantigens, bioluminescence imaging analyses suggest that CD44high TCM also mediate an abortive alloresponses upon transfer into allogeneic recipients. Using an in vivo functional assay, we further demonstrated that alloreactive CD44high TCM lost the reactivity over time, suggesting a mechanism by which CD44high TCM were able to eliminate host resistance without causing GVHD. In conclusion, these data demonstrate that selective transplantation of CD44high TCM is able to efficiently separate anti-tumor effects from GVHD. Disclosures:No relevant conflicts of interest to declare.